Caffeine for apnea of prematurity: a subgroup analysis of the CAP trial

The Caffeine for Apnea of Prematurity (CAP) trial, published in 2006, compared short- and long-term outcomes in a large population of preterm infants treated with caffeine with those of babies receiving a placebo. Previous experimental and clinical studies suggested that the benefits and risks of caffeine may vary according to the respiratory status and postnatal age of the infant. Moreover, different trials and meta-analyses have examined whether safety and efficacy of methylxanthines are related to the specific clinical indication for commencement of treatment but these studies had limited statistical power due to the small number of patients enrolled.
The CAP eligibility criteria were broad and led to the inclusion of about 2000 infants at varying levels of respiratory support and different ages at first treatment. The CAP investigators conducted a post-hoc analysis of the CAP trial results to determine the short- and long-term effects of caffeine according to the clinical subgroups of: (1) indication for commencing study medication (apnea treatment, apnea prevention, or facilitation of extubation); (2) level of respiratory support at randomization (endotracheal tube, non-invasive ventilation, or none); and (3) age at commencement of study drug (early vs. late (<3 vs ≥3 days)).
Overall, the clinical indication for starting study drug did not show any significant impact on the treatment benefits, but the size and direction of the caffeine effects were dependent upon the level of respiratory support and age at randomization. Infants receiving respiratory support, both via endotracheal tube and non-invasive ventilation, appeared to derive greater long-term neurological benefits in terms of death or major disability (P=0.03) and cognitive delay (P=0.02) as compared to infants not requiring any positive pressure ventilation (PPV). In addition, early initiation of caffeine treatment resulted in a larger reduction in the number of days of respiratory support. Indeed, postmenstrual age at time of discontinuing PPV was lower in the early (<3 days) than in the late (≥3 days) treatment group (P=0.01). Mean differences versus placebo were 1.35 weeks (0.90-1.81) and 0.55 weeks (–0.11-0.99) for early and late age of starting treatment, respectively.
The message of the CAP trial for clinicians remains clear: caffeine improves neurodevelopmental outcomes to 2 years of age. While waiting for the results of the 5-year follow-up evaluation, the present subgroup analysis indicates that infants receiving respiratory support could derive more neurodevelopmental benefits and that earlier initiation of caffeine may be associated with earlier discontinuation from ventilatory support.

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